The overall goal of our research is to preserve the integrity of the extracellular matrix of the corneal epithelial basement membrane zone after mustard injury, thereby providing the epithelial cells a substratum on which to recover. Many studies on mustards have focused on their direct impact on epithelial cells. While these cells have ultimate control, their extracellular matrix is a key factor in their survival, and serves an instructive function, facilitating their migration, proliferation, or differentiation and this represents the focus of our studies. Severely altered matrices, which occur as a result of sulfur mustard exposure, appear to lack the appropriate cues, thereby preventing cells from remodeling the tissue back to a normal state. To overcome this, our approach to developing ocular countermeasures is to identify agents that inhibit basement membrane degrading matrix metalloproteinases, in particular, ADAM17/TACE, which cleaves a component of the adhesion complex between the epithelial and stromal cell layers; we are also investigating the role of autophagy in removing cross-linked proteins in vesicant-modified basement membrane. During the next grant period, we will also continue studies working with the Pharmacology and Drug Development Core and the Medicinal Chemistry and Pharmaceutics Core to further develop doxycydine-loaded hydrogels as potential sulfur mustard and nitrogen mustard countermeasures in the cornea. Our preliminary data and published papers demonstrate that these hydrogels are remarkably effective in mitigating sulfur mustard-induced corneal injury; additional studies are needed to improve their efficacy in the rabbit eye model.